帕金森病治疗的新理念——连续多巴胺能刺激

左旋多巴是治疗帕金森病的金标准,但是长期应用后导致运动并发症。近年来研究表明,运动并发症的产生可能与纹状体多巴胺受体长期受到非生理性脉冲样刺激有关,从而提出帕金森病治疗的新理念——连续多巴胺能刺激。改变L-dopa药代动力学特征和给予多巴胺受体激动剂是进行连续多巴胺能刺激的主要手段。连续多巴胺能刺激策略的初步应用显示了良好的临床疗效,但是长期临床疗效仍需要进一步确认。     

治疗早期帕金森病的临床证据

帕金森病是中老年人常见的中枢神经系统退行性疾病,在其早期给予合理的治疗有利于提高患者的生活质量,降低长期用药引起的运动并发症.本文介绍有关早期帕金森病治疗的临床证据,干预措施包括多巴胺受体激动剂,左旋多巴制剂,及多巴胺能神经保护剂等药物及早期步态训练等.     

苯海索联合多巴胺受体激动剂治疗帕金森患者的疗效分析

目的探讨苯海索联合多巴胺受体激动剂治疗帕金森病(PD)患者的临床疗效及安全性。方法选取2017年2月～2019年2月我院收治的PD患者94例,依照随机数字表法分为两组各47例。对照组采用多巴胺受体激动剂治疗,观察组采用苯海索+多巴胺受体激动剂治疗,比较两组临床疗效、不良反应发生率,观察比较治疗前、治疗15d后帕金森病统一评定量表(UPDRS)、帕金森症状量表(Webster)评分。结果观察组治疗总有效率为93.62%,显著高于对照组的76.60%,差异有统计学意义(P<0.05);治疗15d后,观察组UPDRS、Webster评分低于对照组,差异有统计学意义(P<0.05);观察组不良反应发生率为8.52%,与对照组的(12.78%)比较差异无统计学意义(P>0.05)。结论苯海索联合多巴胺受体激动剂治疗帕金森患者疗效显著,可有效改善患者临床症状,且安全性高。     

不宁腿综合症和帕金森病

不宁腿综合症（Restless legs syndrome，RLS），是一种常见的神经系统疾病。随着疾病谱的变化，RLS的发生率逐渐升高。近来，越来越多的文献对这种疾病的临床特征、病理生理改变、影像学发现和临床治疗进行了深入的分析和报道。研究人员发现多巴胺能神经通路功能异常可能是不宁腿综合症和帕金森病的共同潜在致病机制，且治疗帕金森病的多巴胺受体激动剂也能有效的控制不宁腿综合症，故而部分研究人员认为这两种疾病存在某种相关性。因此我们在本文中将对不宁腿综合症和帕金森病的关系进行简要的综述。     

多巴胺受体激动剂治疗早期帕金森病的临床研究

帕金森病（Parkinson＇s disease,PD）是好发于中老年人群的一种神经变性疾病。临床表现主要为运动减少、震颤和肌强直等。本病的晚期致残率较高,其发病率随年龄的增加而上升,我国每年新增的PD患者近10万人。传统的药物治疗一直以左旋多巴制剂替代治疗为主,而多巴胺（DA）受体激动剂最初应用于左旋多巴的辅助治疗。但近年研究表明DA受体激动剂不但能缓解其临床症状,还具有神经保护作用嘲。本研究观察了32例应用DA受体激动剂单药治疗或左旋多巴／苄丝肼（商品名：美多芭）单药治疗的早期PD患者,初步探索DA受体激动剂治疗早期PD的临床疗效。     

吡贝地尔治疗帕金森病的疗效探讨

帕金森病(Pakinson disease,PD)为常见的一种中老年神经系统退行性疾病,随着病程的进展及补充多巴制剂较长时间后,多数患者出现疗效减退及运动波动并发症.吡贝地尔(Piribedil,泰舒达)是继溴隐亭之后一种缓释型多巴胺(DA)受体激动剂,具有治疗震颤、肌强直和运动减少的作用,被认为是目前较好的一种缓释型DA受体激动剂.为此,我们应用法国施维雅药厂生产的吡贝地尔对帕金森病进行治疗探讨.     

帕金森病治疗进展概况

本文简单介绍了原发性帕金森病的流行病学、病因学、危险因素、临床症状、药物治疗和神经外科治疗。药物治疗中介绍了原发性帕金森病的总的治疗原则 ,并对左旋多巴、复方左旋多巴、金刚烷胺、抗胆碱能药物、单胺氧化酶抑制剂、多巴胺能激动剂和儿茶酚 -氧位 -甲基转移酶抑制剂等药物治疗作了介绍 ,同时还介绍了帕金森病神经外科的治疗原则。     

帕金森病治疗进展概况

本简单介绍了原发性帕金森病的流行病学、病因学、危险因素、临床症状、药物治疗和神经外科治疗。药物治疗中介绍了原发性帕金森病的总的治疗原则，并对左旋多巴、复方左旋多巴、金刚烷胺、抗胆碱能药物、单胺氧化酶抑制剂、多巴胺能激动剂和儿茶酚－氧位－甲基转移酶抑制剂等药物治疗作了介绍，同时还介绍了帕金森病神经外科的治疗原则。     

麦角乙脲治疗早期帕金森病

对于帕金森病的治疗,尽管左旋多巴初期疗效较好,但并未能解决该病长期治疗的问题。有学者报告多巴胺受体兴奋剂早期与左旋多巴结合治疗可有效地解决这一问题。为进一步阐明这一点,作者对90例帕金森病者进行了随机前瞻性研究,比较单独用麦角乙脲(多巴胺受体兴奋剂)或早期麦角乙脲与左旋多巴联用或单用左旋多巴长期治疗的效果。     

孤儿核受体在帕金森病发病中的作用

孤儿核受体(retinoid-relatednuclearorphanreceptor,Nurr1),是一种配体调节的转录因子,其对中脑多巴胺能神经元的发育和存活是很重要的。就孤儿核受体对多巴胺能神经元的发育的影响以及对以黑质多巴胺能神经元损害为特征的帕金森病的影响做一综述。     

酪氨酸羟化酶修饰人脐血间充质干细胞移植帕金森病大鼠纹状体内的多巴胺含量

背景：研究表明,干细胞治疗比药物治疗更接近于恢复患者的生理模式,细胞移植治疗已逐渐成为一种趋势。目的：观察酪氨酸羟化酶修饰的脐血间充质干细胞移植后帕金森病大鼠纹状体内多巴胺含量的变化。 方法：将酶切鉴定后的新构建质粒pEGFP-C2-TH经电穿孔法转染第3代脐血间充质干细胞,注射到帕金森病大鼠右侧脑室,对照组注入PBS。观察移植细胞在大鼠脑组织内的迁移情况,高效液相色谱仪检测大鼠纹状体内多巴胺的含量。 结果与结论：质粒pEGFP-C2-TH转染的脐血间充质干细胞移植后8周,细胞逐渐向脑室转移,12周时迁移至皮质,可表达酪氨酸羟化酶抗原,且实验组多巴胺含量明显高于对照组（P＜0.05）。结果表明酪氨酸羟化酶修饰的脐血间充质干细胞经脑室移植对帕金森病大鼠具有明显的治疗作用。     

小胶质细胞介导帕金森病模型小鼠的炎症损伤

背景:研究表明帕金森病的黑质纹状体存在小胶质细胞的激活,但其释放炎症因子在帕金森病发病过程中的作用尚不明确。目的:观察小胶质细胞激活所释放的两种炎症因子整合素α及肿瘤坏死因子α在小鼠黑质部位的蛋白表达及酪氨酸羟化酶的蛋白表达。方法:将C57BL/6小鼠经腹腔注射百草枯(10mg/kg),设为帕金森病模型组,并设置对照组,观察两组小鼠行为活动。用高效液相法测定小鼠黑质纹状体多巴胺的含量。采用免疫组织化学法检测黑质部位酪氨酸羟化酶、整合素α及肿瘤坏死因子α蛋白表达。结果与结论:百草枯可造成帕金森病模型组小鼠运动减少,并伴有运动迟缓、震颤、探嗅、竖毛及尾巴硬类似于帕金森病样的行为表现,并且脑内黑质纹状体多巴胺含量降低(P<0.05),酪氨酸羟化酶蛋白表达降低(P<0.05),整合素α和肿瘤坏死因子α蛋白表达增加(P<0.05),肿瘤坏死因子α在模型组小鼠黑质纹状体有阳性表达,且主要分布在小胶质细胞上。结果表明小胶质细胞介导的炎症损伤参与了帕金森多巴胺能神经元的损害过程。     

小胶质细胞与帕金森病(英文)

背景:由于多巴胺能神经元对氧化应激特别敏感,小胶质细胞的重要特点之一是易活化,而活化的小胶质细胞是氧自由基产生的主要来源,因此小胶质细胞的激活在帕金森病的发病和病情进展中具有更加重要的作用。目的:总结讨论小胶质细胞与帕金森病的相互关系。方法:由第一作者用计算机检索中国期刊全文数据库(CNKI:2000/2010)和Medline数据库(2000/2010),检索词分别为"帕金森病,小胶质细胞"和"Parkinson’sdisease,Microglia",从小胶质细胞激活后产生的细胞因子、毒性物质对帕金森病发病的影响与抑制小胶质细胞的激活,阻止神经毒性因子的损害作用进而阻止帕金森病的进展2方面进行总结,对小胶质细胞与帕金森病的相互关系作相关介绍。结果与结论:共检索到112篇文章,按纳入和排除标准对文献进行筛选,共纳入27篇文章。结果表明小胶质细胞的激活会损伤多巴胺能神经元,从而引发帕金森病。而帕金森病的发生发展则使多巴胺递质进一步减少、继续损伤多巴胺能神经元并释放炎性因子促使小胶质细胞激活。抑制小胶质细胞的激活则有可能阻止帕金森病的进展。     

Dopamine and migraine: a review of pharmacological, biochemical, neurophysiological, and therapeutic data

The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele Nco I C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while there is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hvpersensitivity.     

Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia

Introduction and aim: Dopamine agonists have been reported to increase the risk of cardiac valve regurgitation in patients with Parkinson’s disease. However, it is unknown whether these drugs might be harmful for patients with hyperprolactinaemia (HyperPRL). The aim of the study was to evaluate whether HyperPRL patients treated with dopamine agonists had a higher prevalence of cardiac valves regurgitation than that of general population. Methods and patients: One hundred consecutive patients (79 women, 21 men, mean age 41 ± 13 years) with HyperPRL during treatment with cabergoline were enrolled in an observational case–control study and compared with 100 matched normal subjects (controls). Valve regurgitation was assessed by echocardiography according to the American Society of Echocardiography recommendations. Results: Seven HyperPRL patients (7%) and six controls (6%) had moderate (grade 3) regurgitation in any valve (p = 0.980). All were asymptomatic and had no signs of cardiac disease. Mean duration of cabergoline treatment was 67 ± 39 months (range: 3–199 months). Mean cumulative dose of cabergoline was 279 ± 301 mg (range: 15–1327 mg). Moderate valve regurgitation was not associated with the duration of treatment (p = 0.359), with cumulative dose of cabergoline (p = 0.173), with age (p = 0.281), with previous treatment with bromocriptine (p = 0.673) or previous adenomectomy (p = 0.497) in patients with HyperPRL. Discussion: In conclusion, treatment with cabergoline was not associated with increased prevalence of cardiac valves regurgitation in patients with HyperPRL. Mean cumulative dose of cabergoline was lower in patients with HyperPRL than that reported to be deleterious for patients with Parkinson’s disease: hence, longer follow‐up is necessary, particularly in patients receiving weekly doses > 3 mg.     

Rotigotine transdermal patch for the treatment of Parkinson’s Disease

Rotigotine, a non‐ergot dopamine agonist, has been developed as a novel transdermal formulation. The rotigotine transdermal patch has received EMEA marketing authorization for the treatment of adult patients with early or advanced Parkinson’s disease (PD) or with moderate to severe restless legs syndrome (RLS). FDA originally granted a marketing authorization for early PD, which was later suspended, and is now studying the authorization for RLS. The aim of this review is to review the pharmacokinetics, pharmacodynamics as well as the clinical efficacy and tolerability of the rotigotine transdermal patch in PD. Source material was identified using a PubMed search for the term ‘rotigotine’ and PD. Articles published up to January 2011 or abstract submitted to most relevant international neurology congresses were reviewed. The rotigotine transdermal patch is efficacious for the treatment of PD. Tolerability profile appears to be well within the range of that observed with other non‐ergot dopamine agonists in PD. Application‐site reactions were the most frequent adverse event, and they were considered mild to moderate in the majority of cases. The rotigotine transdermal patch offers a safe and efficacious alternative for the treatment of PD. Further studies should focus on the possibility that continuous dopamine stimulation by means of the transdermal patch has any influence on levodopa‐related motor complications.     

Neuroprotective therapy in Parkinson disease

During the past decade, there has been a remarkable progress in our understanding of the biology of Parkinson disease (PD), which has been translated into searching for novel therapy for PD. Much focus is shifted from the development of drugs that only relieve PD symptoms to new generation of remedies that can potentially protect dopaminergic neurons and modify the disease course. Several novel therapeutic approaches have been tested in preclinical experiments and in clinical trials, including molecules targeting on genes involved in the pathogenesis of the disease, neurotrophic factors critical for dopaminergic neuron survival and function, new generation of dopamine receptor agonists that may possess neuroprotective effects, and agents of antioxidation, antiinflammation, and antiapoptosis. The results of these studies will shed new light to our hope that PD can be cured in the future.     

Dopamine et douleur : une revue de littérature

This article presents a review of the literature that indicates a key role for dopamine in pain perception: (i) positron emission tomography studies targeting D₂ dopaminergic receptors; (ii) genetic studies of dopamine receptors and one of the proteolytic enzymes that breaks them down; (iii) studies measuring the effects of anti-parkinson agents, bupropion and antipsychotic drugs on pain; and (iv) studies inducing experimental pain in cases of neuropsychiatric disorders (Parkinson’s disease and schizophrenia) in which dopamine is disrupted. Our overall hypothesis is that dopamine plays a role in pain regulatory mechanisms, suggesting further investigation of this neurotransmitter’s influence in pain disorders (such as fibromyalgia) in which those mechanisms function abnormally.     

The efficacy and feasibility of aquatic physiotherapy for people with Parkinson’s disease: a systematic review

Abstract

Purpose: To critically evaluate the literature regarding the efficacy and feasibility of aquatic physiotherapy in people with Parkinson’s disease.

Method: Relevant studies were identified through searches in nine health-related databases. Two independent reviewers assessed study quality using either the PEDro scale or a customised tool for safety and feasibility.

Results: Database searches yielded 88 articles, of which 10 met the inclusion criteria. Studies varied greatly in methodology, quality, interventions and outcome measures. Study quality was generally low in items reporting on safety precautions, adverse events, attrition, and adherence. Results suggest that aquatic physiotherapy may have a positive effect on motor symptoms, quality of life and balance.

Conclusions: Aquatic physiotherapy may improve aspects of motor performance, quality of life and balance in people with Parkinson’s disease, however, it remains unclear whether it is a safe and feasible treatment modality. The development of standardised outcome measures for people with Parkinson’s disease (unified Parkinson’s disease rating scale and Parkinson’s disease questionnaire-39) would aid study comparability and validate study outcomes. As safety criteria was grossly underreported, guidelines for mandatory reporting of safety criteria are essential to make conclusions regarding the feasibility of aquatic physiotherapy for people with Parkinson’s disease.

• Implications for Rehabilitation

• Aquatic physiotherapy may be a beneficial treatment modality for people with Parkinson’s disease.

• A minimum data set that includes the unified Parkinson’s disease rating scale and Parkinson’s disease questionnaire 39 is required to aid future meta-analysis and to allow more definitive conclusions to be made regarding aquatic physiotherapy for people with Parkinson’s disease.

• People with Parkinson’s disease are a vulnerable population, where safety within an aquatic physiotherapy program needs to be well documented and addressed.

     

D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkeys

Selective D(1) dopamine receptor agonists exert antiparkinsonian effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's disease and in human Parkinson's disease. Motor impairment in idiopathic Parkinson's disease progresses from mild to severe, but the therapeutic potential of D(1) dopamine receptor agonists in early and advanced stages of parkinsonism is not known. To compare the effectiveness of D(1) agonists at different levels of impairment, we developed a model of mild and advanced parkinsonism in nonhuman primates and a rating scale that differentiated the two models. D(1) dopamine receptor agonists (SKF 81297, dihydrexidine) and D(2) dopamine receptor agonists [quinelorane, (+)-PHNO were administered to monkeys (Macaca fascicularis) displaying either mild parkinsonism (two doses of 0.6 mg/kg i.v. MPTP 1 month apart) or advanced parkinsonism (three doses of 0.6 mg/kg i.v. MPTP within 10 days). In normal monkeys (n = 3), SKF 81297 and dihydrexidine did not promote increased motor activity. In advanced parkinsonism (n = 4), D(1) and D(2) dopamine agonists effectively reversed the motor deficits. In contrast, the therapeutic benefits of D(1) agonists SKF 81297 and dihydrexidine were relatively limited in mild parkinsonism (n = 4). The D(2) agonists quinelorane and (+)-PHNO alleviated some symptoms in mild parkinsonism but also reduced balance and induced more dyskinesias than did D(1) agonists. Mild and advanced parkinsonism in nonhuman primates can be produced with fixed dosing regimens of MPTP. Based on the therapeutic efficacy and side effect profiles derived from these models, D(1) agonists are more promising for the treatment of advanced than of mild Parkinson's disease.